Researchers find evidence that virtually untreatable strains of tuberculosis have become established and are circulating in the Eastern Cape Province of South Africa. This may also help to explain the poor outcomes of XDR-TB treatment; highlighted in a separate report from KwaZulu-Natal where only one in five adult cases had a successful treatment outcome.
When reports of 'totally drug-resistant' tuberculosis from India hit the news about a year ago (see blog), there was acknowledgement that similarly-resistant Mycobacterium tuberculosis strains had probably become established elsewhere. This was particularly so in South Africa, where efforts to control multidrug-resistant TB (MDR) and extensively drug-resistant TB (XDR-TB) have been characterised by poor treatment outcomes. Now researchers from Stellenbosch University have used molecular techniques to provide strong evidence not only that such strains can been detected in the Eastern Cape Province but also that transmission of these strains has been occurring.
The study by Marisa Klopper and colleagues, published in Emerging Infectious Diseases, reports analysis of 651 M. tuberculosis strains isolated from sputum cultures between July 2008 and July 2009 at the main provincial TB laboratory. Of the 342 strains that were resistant to rifampicin and isoniazid (MDR-TB) on routine testing, molecular analysis showed that 60% had pre-XDR-TB or XDR-TB (i.e. mutations conferring resistance to either or both a second-line injectable and fluoroquinolone). Increasing drug resistance was associated with one particular genotype of M. tuberculosis (atypical Beijing strain). Moreover, molecular analysis showed that the pre-XDR-TB and XDR-TB isolates were genetically very closely related, providing reasonable evidence that there had been transmission of these resistant strains (and that they had not all emerged independently in people exposed to second-line drugs). It was noteworthy that these strains were found in several districts within the province, rather than being clustered in one geographic area. The study was purely a laboratory-based study and there was no linkage to individual clinical information which to some extent limits interpretation of the data.
Of the 103 atypical Beijing XDR-TB strains, the vast majority (95%) had evidence on genotypic testing of resistance to all the drugs tested: isoniazid (katG and inhA gene), rifampicin (rpoB), ethambutol (embB), pyrazinamide (pncA), streptomycin (rrs500), amikacin (rrs1400), kanamycin (rrs1400), capreomycin (rrs1400), ethionamide (inhA) and ofloxacin (gyrA). It should be noted, however, that there was poor correlation between the presence of genetic mutations and phenotypic drug susceptibility for ethambutol, ethionamide and capreomycin. Only a sub-sample was tested for susceptibility to p-aminosalicylic acid (PAS) using phenotypic methods and, of those, 20% were defined as resistant. No genotypic or phenotypic test was performed for cycloserine/terizidone.
In a separate study from KwaZulu-Natal, also published in Emerging Infectious Diseases, Max O'Donnell and colleagues present outcomes for 114 adults treated for XDR-TB at the provincial drug-resistant TB referral hospital in KwaZulu-Natal. All cases started treatment between December 2006 and October 2007 and outcomes were ascertained from routine hospital records. Most were treated with a standardised regimen consisting of capreomycin, pyrazinamide, PAS, ethionamide, ethambutol and cycloserine or terizidone. There was no laboratory data regarding drug susceptibility over and above the routine diagnostic tests used to identify the XDR-TB. Only around one in five cases (22%) had a successful outcome (cure or completion) - 42% died, 17% defaulted and 19% failed treatment. Of the 42 cases with culture conversion during treatment, one in six showed culture reversion, suggesting the emergence of additional resistance during treatment.
The data provided in these two papers highlight the challenges faced in the response to drug-resistant TB in South Africa. Improved diagnostic and therapeutic strategies are urgently needed to address this problem. There is now a substantial body of evidence demonstrating poor outcomes with standardised drug regimens for MDR- and XDR-TB. The development of molecular tests that can detect the genetic mutations associated with resistance to second-line drugs offers the opportunity for more rapid detection of specific resistance patterns and might allow individually tailored regimens, but whether or not this leads to better outcomes need to be explored in rigorous studies. Collection and curation of genetic data might allow identification of individual marker mutations that are associated with particular patterns of drug resistance - this was seen with the Eastern Cape isolates (and previous research by the same group) where the presence of mutations in the inhA promoter region was associated with pre-XDR- and XDR-TB. Even with advances in diagnostics, however, there is a pressing need for new anti-TB drugs and regimens to offer a realistic hope of improved outcomes. Whilst there are new drugs undergoing clinical trials, the global TB community is pushing for accelerated evaluation and approval. These results from South Africa show us exactly why people cannot wait.
Klopper M, Warren RM, Hayes C, van Pittius CG, Streicher EM, Muller B, Sirgel FA, Chabula-Nxiweni M, Hoosain E, Coetzee G, van Helden PD, Victor TC, Trollip AP. Emergence and spread of extensively and totally drug-resistant tuberculosis, South Africa. Emerg Infect Dis 2013 Mar
O'Donnell MR, Padayatchi N, Kvasnovsky C, Werner L, Master I, Horsburgh CR. Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection. Emerg Infect Dis 2013 Mar